Inclusion Criteria

Inclusion Criteria

- Signed informed consent approved by the Institutional Review Board prior to
participant entry

- Age ≥ 18 years.

- Karnofsky ≥ 70%

- Participant must be able and willing to comply with study and/or follow‐up procedures
Participants must have histologically confirmed diagnosis of GBM patients with either
grade III or IV malignant glioma are eligible to the Phase I portion of the study)
and radiographic evidence of recurrence or disease progression (defined as either a
greater than 25% increase in the largest bidimensional product of enhancement, a new
enhancing lesion, or significant increase in T2 FLAIR) following prior therapy (i.e.
chemotherapy, XRT, other investigational therapies).

- No more than 3 prior episodes of progressive disease (patients with more than 3 prior
episodes of progressive disease are eligible for the Phase I portion of this study)

- An interval of at least 4 weeks (to start of study agent) between prior surgical
resection or one week from stereotactic biopsy

- An interval of at least 12 weeks (to start of study agent) from the end of prior
radiotherapy unless there is a new area of enhancement consistent with recurrent
tumor outside of the radiation field, or there is histological confirmation of
unequivocal tumor progression

- From the projected start of scheduled study treatment, the following time periods
must have relapsed: 4 weeks from any investigational agent, 4 weeks from cytotoxic
therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks
from antibodies, or 4 weeks from other anti‐tumor therapies.

- Participants must have recovered to a grade 0 or 1 from the toxic effects of prior
therapy (with the exception of lymphopenia, which is common after therapy with
temozolomide, and alopecia).

- No evidence of hemorrhage on the baseline MRI or CT scan other than those that are ≤
grade 1 and either post‐operative or stable on at least two consecutive scans.
Clinical Labs - performed within 14 days prior to enrollment

- Hematocrit > 29%, ANC > 1,000 cells/μl, platelets > 100,000 cells/μl ;

- Serum creatinine < 1.5 mg/dl, serum SGOT and bilirubin < 2.5 times upper limit of
normal;

- PTT or aPTT ≤ 1.5 times upper limit of normal and INR ≤ 1.5

- Calculated creatinine clearance > 40 mL/min according to the Cockcroft‐Gault formula
OR per 24 hour urine collection

- Urinary protein quantitative value of < 30 mg/dL in urinalysis or <1+ on dipstick,
unless quantitative protein is < 1000 mg in a 24 hour urine sample;

- Participants of child‐bearing potential who have not undergone a bilateral
salpingo‐oopherectomy and are sexually active must consent to use an accepted and
highly effective non‐hormonal method of contraception (i.e. double barrier method
[e.g., condom plus diaphragm]) from signing the informed consent through 6 months
after last dose of study drug.

Exclusion Criteria:

- Prior anti‐angiogenic therapy targeting VEGF or VEGF receptor including prior
bevacizumab.

- Prior AMG 386 therapy or other molecules that inhibit the angiopoietins or Tie2
receptor.

- Co‐medication that may interfere with study results; e.g. immunosuppressive agents
other than corticosteroids.

- Active infection requiring intravenous antibiotics

- Current or within 30 days prior to enrollment treatment with immune modulators such
as systemic cyclosporine and tacrilomus.

- Current us of warfarin sodium or any other Coumadin‐derivative anticoagulant.
Participant must be off Coumadin‐derivative anticoagulants for at least seven days
prior to starting study drug. ow molecular weight heparin is allowed.

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than supportive care or
epidemiologic studies.

- History of clinically significant bleeding within 6 months of enrollment

- History of allergic reactions to bacterially produced proteins

- Known hypersensitivity to any component of bevacizumab (cohort B only)

- Known sensitivity to any of the products to be administered during dosing

- History of venous or arterial thromboembolism within 12 months prior to enrollment.

- Severe hepatic insufficiency (ongoing grade 3 or greater hepatic adverse events) or
known active chronic hepatitis.

- Inadequately controlled hypertension (defined as systolic blood pressure >140 and/or
diastolic blood pressure > 90 mmHg). The use of anti‐hypertensive medications to
control hypertension is permitted.

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- Clinically significant cardiovascular disease within 12 months prior to enrollment,
including myocardial infarction, unstable angina, grade 2 or greater peripheral
vascular disease, cerebrovascular accident, transient ischemic attack, congestive
heart failure, or arrhythmias not controlled by outpatient medication, percutaneous
transluminal coronary angioplasty/stent.

- Evidence of bleeding diathesis or coagulopathy

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment or anticipation of need for major surgical procedure during
the course of the study

- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to study enrollment.

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to study enrollment.

- Serious, non‐healing wound, ulcer (including gastrointestinal), or bone fracture.

- Any condition which in the investigator's opinion makes the subject unsuitable for
study participation.

- Pregnant (positive pregnancy test) or lactating. Refusal or inability to use highly
effective means of contraception (men and women) in participants of child‐bearing
potential.